Disease relevance of CTSK

• This demonstrates that inhibition of cathepsin K leads to an inhibition of this bone resorption marker in OVX rhesus monkeys and strongly suggests that inhibition of cathepsin K is a viable therapeutic approach for the treatment of osteoporosis [1].

High impact information on CTSK

• It was shown that, unlike some peptidic nitrile inhibitors of cysteine proteases, the nitrile moiety of (R)-2 is not converted to the corresponding amide 3 by cathepsin K [1].
• The P2-P3 amide bond of a known amino acetonitrile dipeptide 1 was replaced with a phenyl ring, thereby giving rise to this biaryl series that retained potency vs cathepsin K and showed an improved selectivity profile against other cathepsins [1].
• Rhesus monkey cathepsin K was transiently expressed in Chinese hamster ovary (CHO) cells and found to be secreted as the proenzyme in the culture media and 50% activated to the mature form intracellularly [2].
• Based on our previous study with trifluoroethylamine as a P2-P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of compound 22 (L-873724) as a potent and selective non-basic cathepsin K inhibitor [3].

Chemical compound and disease context of CTSK

• Cathepsin K is a cysteine protease involved in degradation of human type I collagen and plays a primary role in bone resorption [2].

Analytical, diagnostic and therapeutic context of CTSK

• The high similarity between the sequences and the kinetic properties of rhesus monkey and human cathepsin K establishes this monkey species as a suitable animal model for development of novel cathepsin K inhibitors as antiresorptive agents [2].
• We have cloned rhesus monkey cathepsin K by reverse transcriptase-polymerase chain reaction (RT-PCR) from rhesus ovary poly A+ RNA [2].

References